Method of treating cancer with combinations of histone deacetylase inhibitors (HDAC1) substances

ABSTRACT

A method for treating cancer is described using combination therapies comprising the use of hyperbaric oxygen with histone deacetylase inhibitors, with and without glycolytic therapies. The patient is subjected to a hyperbaric environment of substantially pure oxygen. A predetermined dose of one or more HDACI substances is administered to the patient. In addition, glycolitic inhibitors may also be administered. Dosages, pressures, and durations are selected as described herein to have a therapeutic effect on the patient.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/507,950 filed Jul. 14, 2011, the entirety of which is herebyincorporated by reference.

FIELD OF INVENTION

This invention relates to the treatment of patients with cancer,particularly cancer in advanced stages through combination therapiescomprising the use of hyperbaric oxygen with histone deacetylaseinhibitors with and without glycolytic therapies.

BACKGROUND OF THE INVENTION

In 2007, the ten most commonly diagnosed cancers among men in the UnitedStates included cancers of the prostate, lung, colon, rectum, andbladder; melanomas of the skin; non-Hodgkins lymphoma; kidney cancer,mouth and throat cancer, leukemia, and pancreatic cancer. In women, themost common cancers were reported as breast, lung and colon cancer.Overall, 758,587 men were told they had cancer and 292,853 men died fromcancer in the U.S. in 2007. In women there has been a prevalence of6,451,737 advanced cases reported by SEER at CDC. In general there were11,957,599 advanced cancer cases in the US reported in 2010 by CDC andthe incidence has been almost unchanged over the previous 8 years(482,000 cases in 2000 versus 456,000 cases in 2008). There has been anannual percentage change of only (−0.6) between years 1999 to 2008 incancer incidence. Statistics show that deaths caused by advanced cancersfrom all types have not significantly changed since a decade ago, and insome cases, such as lung cancer with increased incidence since 1930, thedeath rate has remained rising, especially among women. As more and morechemotherapy agents are introduced to the market for advanced stages ofdisease, the patient survival rates have remained essentially unchanged.Moreover, the potential toxicity of many chemotherapeutic agents can bea devastating factor both for the clinician and the patient. Thereforethe need for non-toxic therapies, used either alone or in combinationwith traditional chemotherapy, is evident.

Besides chemotherapy agents, many natural and several syntheticmedications have been separately assessed to target cancer in differenttrials. Dichloroacetic acid (DCA), 3 Bromopyruvate (3BP), Sodium phenylbutyrate, and some natural antioxidants such as quercetin as a strongepigenetic modifier and an antioxidant have been used separately inresearch, and several clinical trials have shown promise in treatingpatients with advanced cancer either to achieve a response or increasethe quality of life. Many of such treatments have been examined andcombined with traditional chemotherapies and prove to function aschemosensitizing and radiosensitizing agents increasing their potentialeffect (1), (2), (3), (13), (46).

SUMMARY OF THE INVENTION

Very generally, the method of the invention comprises administering apredetermined dose of one or more HDACI substances to a patient. Thepatient is then subjected to a hyperbaric environment of substantiallypure oxygen. Dosages, pressures, and durations are selected so as tohave a therapeutic effect on the patient.

According to one embodiment of the invention, a predetermined dose of ahistone deacetylase inhibitor (HDACI) substance or substances isadministered to a patient either intravenously or orally. In particular,sodium phenyl butyrate and quercetin have been found to be usefulsubstances. Within substantially one hour of administering thepredetermined substance or substances, the patient is subjected to ahyperbaric environment of substantially pure oxygen at a pressure ofsubstantially one and one half to two atmospheres for a duration ofsubstantially one hour. Preferably, a standard high pressure hyperbaricchamber is used for this step of the method. The predetermined dose isselected as described with more particularity below to have atherapeutic effect upon the patient when used in combination with thehyperbaric environment.

DETAILED DESCRIPTION OF THE INVENTION Histone Deacetylase InhibitorsSodium PhenylButyrate (SPB)

Sodium phenylbutyrate (SPB) is classified by the FDA as an orphan drugfor the treatment of urea cycle disorders. Phenylbutyrate (PB) is aprodrug. In the human body, it is metabolized by beta-oxidation tophenylacetate. Phenylacetate conjugates with glutamine tophenylacetylglutamine, that is eliminated with the urine. Phenylbutyricacid (PBA) has growth inhibitory and differentiation-inducing activityin vitro and in vivo in model systems. It stops the cell cycle in itsG1-G0 phase. PB is an efficient HDACi and induces apoptosis—probably viac-jun N-terminal kinase (JNK). In lung carcinoma cells, 56 p21waf1-mediated growth arrest in MCF-7 cells, tumor necrosis factor(TNF)-α58 or peroxisome proliferator-activated receptor (PPAR)λ-mediatedcell differentiation, and is more potent than phenylacetate in prostatecancer cells, while increasing MHC class I expression (4), (5), (6),(7), (8). PB is converted in vivo into the active metabolitephenylacetate (PA) by β-oxidation in the liver and kidney mitochondria.Most dose-limiting toxicities (DLTs) are fatigue, nausea, andsomnolence. Preliminary studies have been conducted in patients withrecurrent glioblastoma multiform (GBM) (9). Phase I studies have beenconducted in patients with hormone refractory prostate cancers,refractory solid tumor malignancies like colon carcinoma, non-small celllung cancer (NSCLC), anaplastic astrocytoma, GBM, bladder carcinoma,sarcoma, ovarian carcinoma, rectal hemangiopericytoma, and pancreaticcarcinoma, mainly as intravenous infusions but also in AML andmyelodysplastic syndrome (MDS)(10). It works by affecting the NF Kappa-Bpathway and lowering the inflammatory response and down regulating morethan a hundred genes. The optimal dose and place in therapy is yet to bedefined, but oral doses up to 36 grams per day have been used withminimal toxicity. In one study (11), 25 percent of patients had stabledisease for more than 6 months while on the drug. SPB in oral form iswell tolerated and achieves the concentration in vivo that has beenshown to have biological activity in vitro. It has been suggested thatSPB has a role as a cytostatic agent and should be additionally exploredin combination with cytotoxics and other novel drugs. SPB intravenouslyhas been used in advanced solid tumors with a good safety profile (12),(13). However in most studies SPB has been used orally and notintravenously, and certainly has not been combined with other therapiesdescribed here including hyperbaric oxygen.

Quercetin

Quercetin is a polyphenyl extracted from apples. Although there is stilluncertainty about quercetin's effects against cancer, several mechanismshave been suggested. It has been suggested that quercetin may interactwith a variety of cellular receptors, although little evidence iscurrently available. Mechanisms of cancer treatment suggested by Lamsonet al. include inhibition of cellular growth phase at G1 and G2,inhibition of tyrosine kinase to prevent uncontrolled proliferation,influencing estrogen receptors, and interacting with heat shock proteinsto prevent proliferation. Regarding cancer prevention, Li et al. haveshown that quercetin may interact with receptors like Raf and MEK thatare involved in tumor proliferation. Interactions with other receptorsare also suspected, mainly affecting expression of surface receptors andgrowth of cancerous cells. A second theoretical mechanism of cancerprevention is modification of signal transduction. Quercetin is reportedto affect cell cycle regulation, cell death, inflammatory reactions andderivation of new blood supply. There is limited in vivo researchdemonstrating quercetin's ability to treat cancer. One phase 1 clinicaltrial discussed below has used quercetin to treat a range of advancedcancers in humans. This trial determined an effective dosage for a phase2 trial, but did not focus on cancer outcome or survival time.

Ferry et al. conducted an open label, uncontrolled dose-finding clinicaltrial of quercetin as a cancer treatment in 1996. The purpose of thisphase 1 trial was to establish a safe dosage for further studies, andthus it was not designed to track cancer progression. In this trial,increasing values of up to 1700 mg/m2 intravenous quercetin wereadministered for 3 weeks to 50 patients who had cancer deemed no longertreatable by conventional methods. Patients with a variety of cancerswere treated including large bowel, stomach, pancreas, ovarian andmelanoma. None of the patients achieved suppression as defined by theradiological criteria of WHO, but two showed sustained decreases inunique cancer markers following quercetin therapy (one with metastatichepatocellular carcinoma, and the other with stage 4 metastatic ovariancancer that had been previously unresponsive to chemotherapy). Inaddition, tyrosine kinase levels were measured in 11 subjects, and adecrease in 9 was reported. (Tyrosine kinase may lead to theuncontrolled proliferation of cancer by overriding signals that controlcell growth). The authors concluded that this study provides preliminaryevidence suggesting quercetin's ability to inhibit tyrosine kinase, andphase 2 studies should be undertaken at doses no higher than 1400 mg/m2(14). The results of this study have been supported by several in vitrotrials in which quercetin caused suppression of tyrosine kinaseexpression in malignant and non-malignant cells (15).

Two animal studies have been conducted to assess quercetin's ability totreat cancer. One study reported a 20% increase in lifespan afterquercetin was injected peritoneally in mice inoculated with acites tumorcells (16). Another study involving mice inoculated with a humansquamous cell carcinoma line showed selective inhibition of cancergrowth when quercetin was injected interperitoneally, with minimaleffects on surrounding normal cells (17). Additional clinical studiesare needed to confirm these findings and determine if they areapplicable to humans.

It is hypothesized that quercitin can show promising results in treatingalmost every cancer cell due to its genetic regulatory effects (loweringRAS and bc1-2) and epigenetic effect along with chemo sensitizingeffects and estrogen receptor modulation in hormonal dependent tumors.It is also suggested that it has a preventive role in cancer incidence.In one study by Nothlings, U., Murphy, S. P., Wilkens, L. R., Henderson,B. E., Kolonel, L. N. published at American Journal of Epidemiology.2007; 166(8): 924-31, a total of 529 cases of exocrine pancreatic cancerthat arose during the previous 8 years, was tracked through state cancerregistries. Quercetin intake was negatively correlated with pancreaticcancer among current smokers, showing a significantly decreased (0.55)relative risk between the highest and lowest quintiles of intake.

There do not, however, appear to be human studies that have looked atquercetin's effects when used intravenously in conjunction with otherepigenetic therapies (such as sodium phenyl butyrate).

Lipoic Acid

Lipoic acid (LA) is a cofactor of pyrovate dehydrogenase inMitochondria. It is not synthesized in human being and is not availablein enough quantities in diet or food. Naturally occurring lipoic acid isalways covalently bound and not immediately available from dietarysources. Low levels of lipoic acid have been correlated to a variety ofdisease states (18), (19), (20), (21). A study of LA demonstrated themaximum concentration in plasma and bioavailability are significantlygreater than the free acid form, and rivals plasma levels achieved byintravenous administration of the free acid form. Lipoic acid is todayconsidered to be a “conditionally essential nutrient”. LA is generallyconsidered safe and non-toxic. RLA is being used in a federally fundedclinical trial for multiple sclerosis at Oregon Health and ScienceUniversity. R-lipoic acid (RLA) is currently being used in two federallyfunded clinical trials at Oregon State University to test its effects inpreventing heart disease and atherosclerosis. Alpha-lipoic acid isapproved in Germany as a drug for the treatment of polyneuropathies,such as diabetic and alcoholic polyneuropathies, and liver disease.

More recently the primary effect of lipoic acid is revealed to be not asan in vivo free radical scavenger, but rather an inducer of theoxidative stress response as described below used with hyperbaric oxygenpotentiating the oxidation in combination therapy against cancer. It hasbeen shown that Alpha-Lipoic acid induces apoptosis in human coloncancer cells by increasing mitochondrial respiration with a concomitantfree oxygen radical generation. Several studies provide evidence thatAlpha Lipoic acid can effectively induce apoptosis in human colon cancercells by a prooxidant mechanism that is initiated by an increased uptakeof oxidizable substrates into mitochondria (22).

In 2010, studies have shown great promise in using lipoic acid to treata variety of cancer cells in mouse syngenic cancer models: MBT-2 bladdertransitional cell carcinoma, B16-F10 melanoma and LL/2 Lewis lungcarcinoma. Lipoic acid reduced the cell number by 10-50% depending onconcentrations. The efficacy of a combination treatment mainly usinglipoic acid appeared similar to conventional chemotherapy (cisplatin or5-fluorouracil) as it resulted in significant tumor growth retardationand enhanced survival. Such preliminary studies suggest a clinical trialis warranted (23).

Lipoic acid decreases cancer cell viability and increases DNAfragmentation of the cells. In general, Lipoic acid's anticancer effectis mediated by inducing apoptosis through caspase-independent andcaspase-dependent pathways, which is mediated by intracellular Ca (2+)(24).

Recently there has been a great effort by the pharmaceutical industry tomanufacture expensive drugs that have histone deacetylase inhibitoryeffect. New chemotherapy agents, Hydroxamic derivatives such as LBH 589,and Vorinostat have been suggested to be effective against variety ofcancers. It is shown that histone deacetylase inhibitors (HDACI), alsoinhibit angiogenesis (25). Using lipoic acid and Butyrate in combinationcan enhance such effect which, independent from their anti apoptoticeffect, is considered a new cutting edge method to inhibit metastasis ofcancer.

Effects of Hypoxia

Free radicals and Hypoxia can increase the damage to mitochondrial DNAand produce undesirable changes in epigenetics related to risk of cancergrowth and metastasis through Hypoxia induced factor one and VEGF.Hypoxia is a common characteristic of locally advanced solid tumors thathas been associated with diminished therapeutic response and, morerecently, with malignant progression, that is, an increasing probabilityof recurrence, locoregional spread, and distant metastasis. Emergingevidence indicates that the effect of hypoxia on malignant progressionis mediated by a series of hypoxia-induced proteomic and genomic changesactivating angiogenesis, anaerobic metabolism, and other processes thatenable tumor cells to survive or escape their oxygen deficientenvironment. The transcription factor hypoxia-inducible factor 1 (HIF-1)is a major regulator of tumor cell adaptation to hypoxic stress. Tumorcells with proteomic and genomic changes favoring survival under hypoxicconditions will proliferate, thereby further aggravating the hypoxia.The selection and expansion of new (and more aggressive) clones, whicheventually become the dominant tumor cell type, lead to theestablishment of a vicious circle of hypoxia and malignant progression(26). Hypoxia increases tissue factor expression by malignant cellswhich enhances tumor cell-platelet binding and hematogenous metastasis(27). Hypoxia, whatever its duration, rapidly increases the nuclearcontent of HIF-1 as well as the mRNA levels of erythropoietin and VEGF.The transcriptional factor hypoxia-inducible factor-1 (HIF-1) plays animportant role in solid tumor cell growth and survival. Overexpressionof HIF-1 alpha has been demonstrated in many human tumors and predicts apoor response to chemoradiotherapy (28).

Hyperbaric Oxygen Therapy

There are studies that suggest that Hyperbaric oxygen therapy (HBOT) canplay a positive role in certain malignancies and significantly increasequality of life in patient when used along with chemotherapy (29),inhibit the certain cancer genes and tumor growth in vitro (30), (31),and reduce the tumor burden and restrict the growth of large tumor cellcolonies (32). It is possible that this effect is through lowering thehypoxia induced factor one which can change the expression in the VEGFgene subsequently involved in tumor metastasis. VEGF is a majorinitiator of tumor angiogenesis (33), (34). Furthermore, it is foundthat VEGF expression is potentiated by hypoxia and that the potentiationof VEGF production in hypoxic areas of solid tumors contributessignificantly to VEGF-driven tumor angiogenesis (35), (36).

However hyperoxia as a result of hyperbaric oxygen also producesreactive oxygen species which can damage tumors by inducing excessiveoxidative stress (37). On the other hand, free radical related lesionsthat do not cause cell death can stimulate the development of cancer andcan promote cancer growth and metastasis (38) and VEGF exocytosisrequires free radicals formation (39). Reactive oxygen species generatemitochondrial DNA mutation and up regulate hypoxia inducible factor-1alpha gene transcription (40). Therefore reducing oxidative damage isbeneficial.

There are available treatments that effectively reduce free radicalproduction and cellular damage. These treatments can potentially modifythe epigenetics and increase the effectiveness of other treatments suchas DCA and 3 BP. As a result combining HBOT with such modality wouldoffer an advantage to each modality.

In accordance with the invention, the use of HDACI's, administeredeither orally or intravenously, in combination with HBOT and,optionally, in combination with other modalities described herein, hasachieved surprising results in treating various forms of cancer. Theresults are particularly surprising in connection with advanced cancersas evidenced by the cases described below. Because each patient isdifferent, the specific patient protocol is adjusted to achieve optimalresults. However, common to all protocols is the underlying method ofthe invention as claimed herein.

Optional Strategies

One strategy to destroy or prevent cancers is by targeting theircellular energy production factories. All nucleated animal/human cellshave two types of energy production units, i.e., systems that make the“high energy” compound ATP from ADP and P (i). One type is “glycolysis,”the other the “mitochondria.” In contrast to most normal cells where themitochondria are the major ATP producers (>90%) in fueling growth, humancancers detected via Positron Emission Tomography (PET) rely on bothtypes of power plants. In such cancers, glycolysis may contribute nearlyhalf the ATP even in the presence of oxygen (“Warburg effect”). Basedsolely on cell energetics, this presents a challenge to identifycurative agents that destroy only cancer cells, as they must destroyboth of their power plants causing “necrotic cell death” and leavenormal cells alone (41).

Dichloroacetic Acid (DCA)

DCA is a byproduct of chlorinization of water. By stimulating theactivity of pyruvate dehydrogenase, DCA facilitates oxidation of lactateand decreases morbidity in acquired and congenital forms of lacticacidosis. The dichloroacetate ion stimulates the activity of the enzymepyruvate dehydrogenase by inhibiting the enzyme pyruvate dehydrogenasekinase Thus, it decreases lactate production by shifting the metabolismof pyruvate from glycolysis towards oxidation in the mitochondria.

Cancer cells change the way they metabolize oxygen in a way thatpromotes their survival. Solid tumors, including the aggressive primarybrain cancer glioblastomamultiforme, develop resistance to cell death,in part as a result of a switch from mitochondrial oxidativephosphorylation to cytoplasmic glycolysis. DCA depolarizes mitochondria,increases mitochondrial reactive oxygen species, and induces apoptosisin glycolytic cancer cells, both in vitro and in vivo. DCA therapy alsoinhibits the hypoxia-inducible factor-1 alpha, promoted p53 activation,and suppressed angiogenesis both in vivo and in vitro (42). There issubstantial evidence in preclinical in vitro and in vivo models that DCAmight be beneficial in human cancer (43), (44), (45). Furthermore, aspredicted, activating mitochondria by DCA increases oxygen consumptionin the tumor and dramatically enhances the effectiveness ofhypoxia-specific chemotherapies in animal models (46). In laboratorystudies of isolated cancer cells grown in tissue culture, DCA restoresthe original metabolism, and promotes their self-destruction. This hasled to the use of DCA for treating cancer, by individuals experimentingwith it themselves, by doctors administering it to patients, byscientists testing it in cancer tissue cultures in cell culture and inmice, and in human Phase II studies. A phase one study published inJanuary 2007 by researchers at the University of Alberta, who had testedDCA on cancer cells grown in mice, found that DCA restored mitochondrialfunction, thus restoring apoptosis, allowing cancer cells toself-destruct and shrink the tumor. Akbar and Humaira Khan have, since2007, treated cancer patients using DCA off-label at their privateclinic, Medicor Cancer Centres, in Toronto. They have treated severaltypes of cancer and revealed that some patients “are showing variedpositive responses to DCA including tumor shrinkage, reduction in tumormarkers, symptom control, and improvement in lab tests.” DCA hasimproved certain biochemical parameters, but it has not demonstratedimproved survival. The mitochondria-NFAT-Kv axis and PDK are importanttherapeutic targets in cancer; the orally available DCA is a promisingselective anticancer agent (47). However there are no studies inliterature in regards to using DCA intravenously to maximize its effectwhen combined with other treatments such as 3 BP or SPB intravenously.

3 Bromopyruvate (3BP)

3-bromopyruvate (3BP), a hexokinase inhibitor, lowers the ATP productionin cancer cell and has shown great promise in animal studies either usedas intra arterial or intratumoral injection. 3-bromopyruvate (3-BrPA), alactic acid analog, has been shown to inhibit both glycolytic andmitochondrial ATP production in rapidly growing cancers (48), leavenormal cells alone, and eradicate advanced cancers (19 of 19) in arodent model (49). Recent research in tumor metabolism has uncoveredcancer-cell-specific pathways that cancer cells depend on for energyproduction. 3-bromopyruvate (3-BrPA), a specific alkylating agent andpotent ATP inhibitor, has been shown both in vitro and in vivo todisrupt some of these cancer-specific metabolic pathways, therebyleading to the demise of the cancer cells through apoptosis. As analkylating agent and a potent inhibitor of glycolysis, it has recentlybeen exploited to target cancer cells, as most tumors depend onglycolysis for their energy requirements. The anticancer effect of3-bromopyruvate is achieved by depleting intracellular energy (ATP)resulting in tumor cell death. The principal mechanism of action andprimary targets of 3-bromopyruvate, and the impressive antitumor effectsof 3-bromopyruvate in multiple animal tumor models, have been discussedrecently. The primary mechanism of 3-bromopyruvate is via preferentialalkylation of GAPDH. 3-bromopyruvate mediates cell death linked togeneration of free radicals. Research also has revealed that3-bromopyruvate induces endoplasmic reticulum stress and inhibits globalprotein synthesis, further contributing to cancer cell death. Therefore,studies reveal the tremendous potential of 3-bromopyruvate as ananticancer agent (50).

Also there is interest in researching transport ATPase that has seentremendous progress. These ATPases driven in reverse by a protongradient have the capacity to interconvert electrochemical energy intomechanical energy and finally into chemical energy conserved in theterminal bond of ATP (51). It is suggested that 3BP inactivatesH+-vacuolar ATPase, the enzyme that makes certain compartments in thecell acidic. Inactivation probably involves alkylation of the enzyme ona thiol group, essential for H+-ATPase activity for dithiothreitolsecured complete protection from 3-Br PA inactivation. The findings arediscussed with regards to a possible involvement of lysosomedestabilization in 3-Br PA induced cell death (52). Studies at JohnsHopkins University (53) and (54) recently have shown efficacy and doserelated response when 3 BP is used as even a single therapy, when usedintraarterially. However, its role in more aggressive cancers as a solotreatment is not supported. Also its intravenous application has notcaused tumor regression due to lower concentration at the target site.However, if used intravenously, combined with other therapies describedhere, a different scenario results. This may theoretically be due to anadditive or synergistic effect on Mitochondria.

Octreotide

Octreotide (brand name Sandostatin,) is an octapeptide that mimicsnatural somatostatin pharmacologically, though it is a more potentinhibitor of growth hormone, glucagon, and insulin than the naturalhormone. Octreotide is absorbed quickly and completely aftersubcutaneous application. Maximal plasma concentration is reached after30 minutes.

Oncogenes express proteins of “Tyrosine kinase receptor pathways”, areceptor family including insulin or IGF-Growth Hormone receptors. Otheroncogenes alter the PP2A phosphatase brake over these kinases.Octreotide has been used in variety of medical conditions since 1979.Since it inhibits secretion of insulin and also acts as a suppressingagent for Insulin growth factor one (IgF1), its use has been suggestedin a variety of Glycolytic cancers. Octreotide is found to havetherapeutic application beneficial to patients as shown by experimentson animals (55).

GH hormone induces in the liver, the synthesis and release of insulinlike growth factor (IGF). The latter activates, like insulin, theIGF-tyrosine kinase receptors (IGFR), triggering the MAP kinase-ERKmitogenic signal. In normal physiology GH stimulates a triglyceridelipase in adipocytes, increasing the release of fatty acids and their βoxidation. In parallel, GH would close the glycolytic source of acetylCoA, perhaps inhibiting the hexokinase interaction with themitochondria. This effect, which renders apoptosis possible, does notoccur in tumor cells.

GH mobilizes the fatty acid source of acetyl CoA from adipocytes, whichshould help the formation of ketone bodies. But since citrate synthaseactivity is elevated in tumors, ketone bodies do not form. Hence,butyrate cannot inhibit histone deacetylase (HDAC), the enzyme cutsacetylated histone tails, this will silence several genes like PETEN,P53, or methylase inhibitory genes. Therefore combining the histonedeacetylase inhibitors with Octreotide can have a significant additiveeffect on glycolytic tumors.

There appears to be a correlation between IgF1 receptors and thebehavior of the cancer cell. The surface distribution of IGF-IGFR maydetermine if a cell is sterile or endowed with a mitotic potential (55).Therefore, using octreotide along with other combination therapies canpotentially change the cancer cellular motivation to differentiateFinally, the recent discovery of a population of Dwarfs with no GHreceptors, which does not develop cancers, illustrates the GH/IGFprediction, establishing a link between ancient and recent biochemicalobservations on tumors (56).

Finally there are studies that have suggested a correlation between boththe cancer risk as well as the cancer prognosis with the serum IgF-1level in human (57). For example observations implicate IGF-I as animportant factor during the initiation and progression of primaryprostate cancer and provide evidence that there is a strong selectionagainst expression of IGF1R and IGF2R in metastatic andandrogen-independent disease (58), (59). Growing links between insulinand the etiology as well as prognosis in colon, prostate, pancreatic,and, particularly, breast cancer are reviewed. Of particular concern isthe evidence that elevated IGF-1 may interfere with cancer therapy,adversely affecting prognosis (60).

Octreotide used in protocols described below demonstrates theeffectiveness of such treatment in lowering the IgF-1 significantly.

EXAMPLES

Based on above facts, such substances have been employed usingIntravenous and oral targeted therapies to reduce anabolic glycolysis inpatients with cancer along with epigenetic treatments with HDACI andhyperbaric oxygen. These treatments can increase quality of life and canimprove the patient survival. More particularly, an integrative cancercare/approach was undertaken to treat patients who referred for suchintervention voluntarily. As of October 2011, 40 patient charts wereselected randomly and reviewed. The inclusion criteria were diagnosis ofcancer. No patients were excluded. Patients were aged 27 to 83 years.All were diagnosed by their oncologist/physician and were offeredstandard conventional treatment of surgery, traditional chemotherapy orradiation. Out of 40 patients 20 of them refused standard care or therewas no conventional option available for them due to severity of thedisease. Out of 40 patients, 23 of them had advanced stage disease withmicro or macro multiple metastasis at the time of referral, beforestarting the treatment. 19 of these patients (47 percent) had alreadybeen treated with multiple chemotherapy agents unsuccessfully and hadprogression or recurrence of disease manifested by their tumor markersor scans.

The patients were managed based on unique developed protocols that weredesigned in correlation with available research studies and clinicaltrials that implicate using specific natural and synthetic IV therapies.IV therapies are targeted at epigenetic level and consist ofantioxidants, quercetin, DCA, sodium phenyl butyrate, and lipoic acidseparately or in combination. All patients received one or more of suchtreatments. The most effective synergistic combination was found to beintravenous sodium phenyl butyrate and quercetin. Doses of eachtreatment remained the same or close on each treatment, Quercetin wasgiven intravenously at the dose 0.5 to 1.0 gram (50 mg/ml). Whenadministered, SPB was dosed at 5 to 10 gram (25 to 50 ml of 200 mg/ml,When administered, DCA was dosed at 500 mg to 6 gram (maximum 100/kg)When administered, lipoic acid was given at 600-1000 mg. Hyperbaricoxygen treatment was applied, with standard 1.5 to 2.0 atmospherepressure for 45-90 minutes (average 60 minutes) on each session. Whenadministered octreotide was given subcutaneously at 50-400 mcgs.

All patients started the program after educating them about theirpossible options of conventional and non conventional treatments andconsents obtained. The progression of disease was measures during thecourse of treatment through tumor markers, Imaging studies and markersfor cancer growth, necrosis, LDH, and inflammation, CRP, as well as theNatural killer cell activity or lymphocyte count and Circulatory tumorcells.

The following results were obtained during or after completing thecourse of therapy:

1) Subjective Increase in QOL (increase energy level, less pain scoresand elevation in mood: 100 percent

2) Immunological response: Increase in Natural Killer cell activity orWBC count: 35% of patients had initial low NK/WBC, all these patientshave increased NK activity after therapy

3) Potential decrease in tumor activity by measuring LDH: 40 percent ofpatients had high LDH, ALL these patients have shown decreased LDH afterthe therapy

4) Response in Tumor markers, enough to qualify for clinical response:50 percent

5) Shrinkage of tumor in radiographic studies: 35 percent

6) Decrease in CRP (correlation with improved survival): 23 percent

7) Decrease in IgF-1: 12 percent of these patients had increased IgF-1,suggested to correlate with prognosis in literature. All these patientshad improved IgF-1 after the treatment

Since patients with cancer may have significant stratifying confoundersin selecting their control group, we used each patient's preinterventional status as the control arm. Patients other stratifyingconfounders did not change during the study.

Results:

1) These data reveals superior response in the group of patientscompared to the controls. In 47 percent of patients treated there was noconventional option available at the time of referral. In this groupresults are far better compared to conventional modalities of treatment.(no treatment option available)2) Patients who received both HBOT and IV therapies did better as far astheir imaging, their quality of life and tumor shrinkage as well ascontrolling their tumor markers than the ones who did the IV therapiesonly.3) Patients with stage four terminal disease receiving the aboveprogram, exceeded response beyond the standard of care expectations, andthe patients who did receive chemotherapy concurrently with abovetargeted therapies had significant improvement in quality of life andchemotherapy response.

CONCLUSION

In an integrative cancer care program that combines hyperbaric oxygentherapy with specific Intravenous antioxidants and epigeneticmodifications, along with intravenous and/or oral DCA and 3BP, patientsurvival as well as quality of life improved significantly. The abovedescribed modality of care was found to be superior to conventionalstandards of care. The exact reasons for this are still uncertain, butcould possibly be due to the conjunctive effect on the cancer cellmitochondria.

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What is claimed is:
 1. A method for treating a cancer patientcomprising: administering therapeutic doses of histone deacetylaseinhibitor (HDACI) substances to the patient, wherein the substancescomprise quercetin and sodium phenyl butyrate, wherein the quercetin andthe sodium phenyl butyrate are each administered intravenously, andwherein the dose of quercetin is 0.5 to 1.0 grams, and the dose ofsodium phenyl butyrate is 5 to 10 grams.
 2. The method of claim 1wherein the substances are co-administered.
 3. The method of claim 1wherein the substances are administered in combination withchemotherapy.
 4. The method of claim 1 wherein the substances areadministered with radiation.
 5. The method of claim 1, furthercomprising administering green tea extract.
 6. The method of claim 1,further comprising administering Epigallocatechin gallate (EGCG).
 7. Themethod of claim 1, wherein the cancer comprises an advanced stage cancerwith micro or macro multiple metastasis.
 8. The method of claim 1,wherein the patient has previously been unsuccessfully treated withmultiple chemotherapy agents and had progression or recurrence ofcancer.